Abstract
BackgroundZalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.MethodsUsing in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies.ResultsZalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug.ConclusionsRTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials.
Highlights
Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma
The DNA damage repair machinery is essential to overcoming Zalypsis-induced DNA damage, suggesting that this damage is mainly due to double-strand breaks (DSBs) [5]
The panel included 22 genes involved in tumor progression, cell adhesion, cell cycle control, and cell signaling: Apaf-1, APC, cdk4, c-Kit, cyclin D1, E-cadherin, MDM2, MLH-1, MSH-2, p14ARF, p15INK4b, p16INK4a, p21cip1, p27kip1, p53, p73, p85, PDGFRα, p60src, PTEN, pAKT, and β-catenin
Summary
Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. Zalypsis is a novel antineoplastic agent currently in phase II clinical development in endometrial and cervical cancer, multiple myeloma, and Ewing’s sarcoma Zalypsis contains a similar chemical scaffold to trabectedin, differing in an additional appended ring [7]. In vitro data suggests that Zalypsis has DNA-binding properties, induces cell cycle arrest, and inhibits transcription, eventually leading to apoptosis [5,11]. Treatment of cells lines with Zalypsis leads to cell cycle delay in S phase, activation of the DNA damage checkpoint, and cell death. Schizosaccharomyces pombe cells containing a RAD51 mutation were found to be extremely sensitive to Zalypsis, suggesting that the compound induces double-strand breaks (DSBs) [5]. The DNA damage repair machinery is essential to overcoming Zalypsis-induced DNA damage, suggesting that this damage is mainly due to DSBs [5]
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